mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

[adreno]

Here might be a clue. Does ME/CFS have anything in common with neurodegenerative diseases? Does it involve misfolding of proteins? Then rapamycin could help by inducing autophagy, and clearing of diseased proteins:

A second hallmark of these diseases is the accumulation and aggregation of misfolded pathogenic proteins. Clearance of disease-associated proteins, such as mutant alpha-synuclein, ataxin-3, tau and huntingtin, can be achieved by up-regulating the bulk protein degradative process of macroautophagy (5). Furthermore, autophagy seems integral to neuronal health as inhibition of autophagy results in neurodegeneration even in the absence of disease (6).

Autophagy is tightly regulated by a number of pathways, of which the most extensively studied involves the protein kinase mTOR (mammalian target of rapamycin), which negatively regulates autophagy. Inhibition of this pathway with the drug rapamycin enhances autophagy (7).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916709/

 

[adreno]

Failed Trash Clean Up

In addition to the making and use of energy, the body’s clean-up process is also affected. Scientists found that failure of the AMPK activation leads to a build-up in cellular trash. The clean-up process, known as autophagy, is on strike. This is problematic because mitochondria require 24/7 clean up in order to maintain efficiency. This means that older, less efficient mitochondria are left with the brunt of the work and new mitochondria are not being made, i.e. less efficienct and more trash. This is a major problem for high energy, high mitochondria dependent organs like the brain, muscles, and heart. This trash makes tissues stiff and damages these proteins. Without AMPK activation, nerves cells are not protected as AMPK protects neurons under pathological conditions. This slippery slope leads to brain fatigue and breakdown in repair, eventually tumbling into neurodegeneration including Alzheimer’s disease. Impaired trash removal in the cells is like trying to make a gourmet meal in a kitchen that has a month’s worth of unwashed dishes piled up. It doesn’t work. This is often the state of health found in people struggling with significant problems with CFS and FM.

http://www.wellnessresources.com/he...d_in_chronic_fatigue_syndrome_and_fibromyalg/

 

[JES]

While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin.[15] Sirolimus treatment may additionally increase the risk of type 2 diabetes.[16] In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.[17]

Quote from wiki page. This does seem somewhat concerning, considering that many with CFS/ME suffer from different forms of hypoglycaemia. Most supplements that have even a small impact on blood sugar, such as alpha-lipoic acid, tend to produce unacceptable side effects for me.

 

[eljefe19]

Quote from wiki page. This does seem somewhat concerning, considering that many with CFS/ME suffer from different forms of hypoglycaemia. Most supplements that have even a small impact on blood sugar, such as alpha-lipoic acid, tend to produce unacceptable side effects for me.

What reduces insulin sensitivity and could help reverse this side effect?

 

[Tunguska]

Quote from wiki page. This does seem somewhat concerning, considering that many with CFS/ME suffer from different forms of hypoglycaemia. Most supplements that have even a small impact on blood sugar, such as alpha-lipoic acid, tend to produce unacceptable side effects for me.

Yeah chronic treatment results in mTorC2 inhibition (Akt may also lower as result in some but not all tissues) and the effect is worst in the liver they say somewhere. But this is the opposite effect to ALA.

"alternate dosing regimens" is the prudent thing. The second study XenForo linked says they administered 2mg rapamycin daily for 0.5-2 years non-stop to SLE patients. I'd rather see studies on the effectiveness of cycled dosing, even if it means higher doses.

 

[msf]

Assuming that Rapamune (sirolimus aka rapamycin) does turn out to be beneficial for a number of people, I don't think there's much chance that this means mTORC1 is actually over-activated in ME/CFS. I'm definitely sticking with it being under-activated/inhibited.

A couple of explanations for why rapamycin might be working are:

1. Perhaps under-activation of mTORC1 in ME/CFS is actually a beneficial adaptation of the body in its attempt to deal with the disease and further inhibition of mTORC1 by rapamycin is helping achieve this goal.

2. Perhaps there is some non-mTORC1 related beneficial effect that rapamycin has that outweighs the seemingly negative effect of inhibition of mTORC1.

Regarding #1, a mouse study found that rapamycin was able to protect cardiac function in a sepsis model by further reducing mTORC1 activity that had already been reduced upon pathological exposure to lipopolysacharride (LPS). (Not sure if it's just a coincidence here that ME/CFS has been found to closely resemble SIRS/sepsis at the mRNA gene expression level.)

Could you remind me again how you came to the conclusion that mTORC1 might be lowered? And where do you expect it to be lowered? It seems that it can be lowered in some tissues but raised in others, as the sepsis paper you mentioned states:

´However, the precise molecular mechanisms remain elusive. mTORC1 signaling activity can be inhibited with LPS in the skeletal muscle cells [5], but which is activated in LPS-treated liver cells and monocytes conversely [5,6]. ´

I think I mentioned in the mTOR thread that mTOR inhibitors might have a positive impact on ME through the antinflammatory effects of inhibiting mTOR itself, and I believe that I may have just come across the actual mechanism. I will write a longer post, or a blog, in the next few days, and try to join it up with some other things.

 

[Tunguska]

It seems that it can be lowered in some tissues but raised in others, as the sepsis paper you mentioned states:

That's more or less what I've personally been assuming ever since this post: http://forums.phoenixrising.me/inde...-encephalopathy-cfs.48446/page-35#post-818517
Because it's hard to see how the B cells could be so persistent without mTorC1 or mTorC2.

But for the liver specifically, doing the opposite is more the usual case than anything, so I wouldn't read into it too much.

 

[Tunguska]

Regarding #2, even though rapamycin inhibits the mTORC1 enzyme complex it actually increases the activity of the upstream Akt regulator enzyme. (The above mouse study also notes this as well.) This is pretty remarkable because most other substances that might inhibit mTORC1 will usually inhibit Akt too (e.g., metformin). So this might be a key aspect to the beneficial effect of rapamycin, assuming it is actually helping.

Wanted to bump this again, in my best estimation I think Akt is the major key to the immediate symptom relief that people are describing both with Rapamycin and mTor activators. It's important to distinguish this from the longer-term effects [and even from post-exercise effects].

This isn't exactly news, it's mostly Alpha Lipoic Acid (AMPK activator) that gives this link. Myself and others have had temporary excellent experiences with it, provided blood sugar if maintained as above, and it clearly can't be because of its role as cofactor, and there are too many other antioxidants to use if it was only that.

The ALA may work just because it increases Akt, here are the studies I accumulated:
https://link.springer.com/article/10.1007/s10863-012-9460-1
https://www.ncbi.nlm.nih.gov/pubmed/11602326
https://www.ncbi.nlm.nih.gov/pubmed/17274632
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331247/
https://www.ncbi.nlm.nih.gov/pubmed/17360480
https://www.ncbi.nlm.nih.gov/pubmed/17274632
https://www.ncbi.nlm.nih.gov/pubmed/18931933
and it inhibits mTorC1 at the same time through AMPK.

In fact inhibiting mTorC1 should provide more energy temporarily to most people's bodies. The only way this would be different in CFS/ME is if mTorC1 itself alone is in fact the most important key to unlocking PDK, so badly that it would counteract its energy-consuming nature - this is what I (and I assume others) had been assuming originally, but it's highly counterintuitive.

mTorC2 however works the opposite way, it increases Akt.

Regardless I think it's the same for Rapamycin. Rapamycin inhibits mTorC2 with chronic use but the dramatic effect is tissue-specific, and furthermore a bunch of studies show that in skeleton/adipose/other tissues, deleting mTorC2 doesn't significantly ruin Akt, because the body has compensatory mechanisms [google this part].

The best of my understanding and the above comes from this single article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031984/
It could use more graphs but the results and discussion are well related.
The bastardized version is, "Akt is the energy producer from substrates; mTorC1 is major energy consumer". They intermingle with FoxO1-3, mTorC2 and AMPK.

I noticed on the forum - this needs a poll or something - people using the mTor activators were taking them before exercise. This is fine for amino acids since they have dual roles and effects, but most mTorC1 activators don't make much physiological sense to take during activity. Normally you'd want to lower mTorC1 during activity, and increase it only during recovery and the rest of the day, and you'd want mTorC1 dominating in the long-term period for CFS/ME.

Again the only thing that would violate this would be a CFS/ME specific mechanism whereby mTorC1 itself - and not Akt - helps unlock PDK. But even in this case it may still make sense to follow normal physiology if your first goal were to lower post-exercise effects.

Akt can in fact activate PDH [and/through lower PDK - sorry this was a typo] by repressing FoxOs and other factors, and it's very logical that it should increase PDH in general. The part that needs clarification is whether mTorC1 itself has any exclusive effect on it that Akt does not.

But in the meantime I think increased Akt is major enough to explain the symptom relief from Rapamycin.

This is speaking largely about normal skeletal tissue, but Akt has tons of other effects such as modulating effects from LPS and immunity.

 

[Tunguska]

Sorry in the 3rd last paragraph I typo'd and wrote PDK instead of PDH.

 

[adreno]

How much ALA have you been using @Tunguska ?

 

[Tunguska]

@adreno I need at very least 300mg R-ALA for effect. I ran out and I'm waiting for a better quality sup: http://nootropicsdepot.com/r-lipoic-acid/ but the dose I'm aiming for is 300-600mg of R-ALA, taken in first half of the day, in one single dose (offset by mTor boosting the rest of the day). That seems high by some standards, but not by diabetes research standards, and I've tolerated this fine before, but sometimes juice needed.

On that page (ignore the chelation comments) someone wrote it may be worth trying it sublingual to avoid reaching the gut, I'd never thought of doing that, don't know if it has any basis, but I'm going to try it.

This range is the same as used for liver and circadian rhythm, which is something for another thread: https://oregonstate.edu/ua/ncs/arch...-helps-restore-synchronize-“biological-clock”

Anyhow, compared to Rapamycin the major difference are super short half-life and benefits to liver.

 

[Jesse2233]

I wonder if positive response to Rapamune is an indicator of positive response to Rituximab, or if the two drugs mechanisms of action are too different to draw an accurate correlation

 

[Tunguska]

I wonder if positive response to Rapamune is an indicator of positive response to Rituximab, or if the two drugs mechanisms of action are too different to draw an accurate correlation

You'd absolutely need lab markers to say. Rapamycin is so much more broader-acting than Rituximab, even if it did fully overlap, symptom relief couldn't tell you, especially not the overnight type. I'm estimating Akt is the biggest factor in the self-reported responses, but even that is a fancy educated guess.

 

[adreno]

@Tunguska

Lots of things to be confused about, for non-biochemists like me. Why would an AMPK activator (ALA, Rapamycin) not inhibit Akt? Normally they do. For instance, vitamin D3 activates AMPK, which in turn inhibits both Akt and mTOR.

So are you only looking for specific AMPK activators that does not inhibit Akt, and are also short-acting, in order to reap the benefits of rebound mTORC1? Again, using vitamin D as an example, this is long-acting, and would constantly inhibit Akt/mTOR. It seems that AMPK might not be a bad thing for us, however. It ramps up glycolysis, for instance.

 

[Tunguska]

@Tunguska

Lots of things to be confused about, for non-biochemists like me. Why would an AMPK activator (ALA, Rapamycin) not inhibit Akt? Normally they do. For instance, vitamin D3 activates AMPK, which in turn inhibits both Akt and mTOR.

There's no quick answer to that. The de facto reference AMPK activator is AiCAR. In an earlier study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618797/ they assumed that

These results demonstrate that AICAR [...] caused dephosphorylation of Akt and GSK3, but this occurred with a time course that was delayed compared with AMPK activation suggesting that AICAR regulated the phosphorylations of Akt and GSK3 independently of its effects on AMPK

and I think this might have been the consensus, that if AMPK activator activates Akt it must be through its own non-AMPK mechanism.

But this gets contradicted later:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955666/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848036/

Our present study has demonstrated that AMPK enhances insulin sensitivity via at least two mechanisms; first, it is involved in direct regulation of PI3K and second, it inhibits mTOR/S6K to suppress negative feedback loop on the regulation of IRS1. While this latter mechanism has been recently defined, it is not clear how AMPK regulates PI3K. As there are several isoforms of PI3K, it will be interesting to determine which isoform of PI3K is the target of AMPK and how AMPK regulates its activity.

So that's an example.

All the studies are complicated by questions about incubation medium and taking cells out of context, and possibly, misinterpretation. mTorC2 and FoxO complicate the picture because they can transiently cause this scenario.

If you go back to basics and see AMPK as a primitive intracellular energy sensor, there's logic in thinking its activation should lead to higher Akt, in the context of extracellular nutrients being available, as long as mTorC1 is concurrently inhibited. Also the article I posted describes a similar but transient scenario from the p.o.v. of FoxO instead of AMPK.

I wouldn't assume most things listed as "AMPK activators" on the web are likely to do this, there are too many factors.

@Tunguska
So are you only looking for specific AMPK activators that does not inhibit Akt, and are also short-acting, in order to reap the benefits of rebound mTORC1? Again, using vitamin D as an example, this is long-acting, and would constantly inhibit Akt/mTOR. It seems that AMPK might not be a bad thing for us, however. It ramps up glycolysis, for instance.

I'm interested in Akt activator / mTorC1 inhibitor combo substance for use during the most active parts of the day - only. First, I think it may simply be more effective/appropriate for activity. If you take into account the AMPK factor, then I believe sufficient dose will emulate benefits of exercise (including on circadian rhythm). You are right in the sense, I was already interested in short-term AMPK activator use, and this provides stronger incentive. The key is temporary use.

About Vitamin D, I have my own doubts about it, I don't take more than 2,000IU per day anymore, and it doesn't even help. It's highly involved with FoxO as well. I was only interested in it insofar as it may be a requirement for thyroid to work apparently (of course T3 is Akt activator).

 

[Tunguska]

I almost forgot, I saw this case recently and thought it was interesting:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941319/
"AMPK-mediated up-regulation of mTORC2 and MCL-1 compromises the anti-cancer effects of aspirin"
"Whereas aspirin inhibits mTORC1, it stimulates mTORC2 kinase activity in AMPK-dependent manner."
hence another way Akt may elevate is simply be mTorC2 non-transiently, although this is liver and didn't read the whole thing yet.

 

[nandixon]

Could you remind me again how you came to the conclusion that mTORC1 might be lowered?

Just from memory, in the Fluge & Mella study, they found increased (gene) expression of the pyruvate dehydrogenase kinases (PDK1, 2 & 4). And they also found increased expression of SIRT4.

The increase in multiple PDKs suggests that the regulator enzyme Akt is inhibited, which in turn suggests that mTORC1, which is immediately downstream of Akt, is under-activated.

Moreover, mTORC1 is a major negative regulator of SIRT4. The increased SIRT4 suggests that mTORC1 is under-activated or inhibited.

Since mTORC1 is positioned between Akt and SIRT4, then with Akt likely inhibited and the level of SIRT4 improperly high, mTORC1 seemingly must be underactivated.

This is borne out by a number of major findings in ME/CFS including decreased natural killer cell activity (mTORC1 is low in this situation) and increased Treg activity (again mTORC1 will be low). I've listed others in the past as well.

(One of the more interesting is Dr Jay Golstein's finding of ketamine being his most successful drug in the course of treating thousands of ME/CFS patients. Ketamine metabolizes to what is probably the most potent mTORC1 activator known, hydroxynorketamine. Of course that could just be a coincidence that it does the opposite of rapamycin.)

I don't think there's much question that mTORC1 being under-activated is the more likely situation. Some questions to ask though are:

How important is that? It may actually be more of a problem that Akt is inhibited, as @Tunguska has suggested.

Is mTORC1 activity being reduced for good reason and might it be helpful to reduce it even further?

Or, assuming that rapamycin is actually helpful in ME/CFS, is it having some other effect beyond mTORC1 inhibition, as @eljefe19 suggested?

 

[msf]

Thanks, that was very informative. I nominate you for the position of biochemistry explainer to the great unwashed of PR.

 

[msf]

Tunguska might be in the running too.

 

[XenForo]

I tried some 500mg of ALA w/ the .5 mg Rapamune and I'd guess it helps me further (with the fatigue.)

I get a headache w/ Rapamune, and take Diamox 250 mg 2x/day and it goes away.

I'm still doing really really well. Completely out of bed all day long, out biking, gardening, lifting weights. I really hope I don't relapse